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Francisco Pellicer,1 Juan M Ortega-Legaspi,2 Rodrigo Martín,3 Sergio Solís-Nájera,4 Lucía Magis-Weinberg,5 Martha León-Olea,6 Ariel Graff-Guerrero,7,8 Camilo de la Fuente-Sandoval,9 Alfredo O Rodriguez3 1Laboratorio de Neurofisiología Integrativa, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, CDMX, México; 2Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 3Departamento de Ingeniería Eléctrica, Universidad Autónoma Metropolitana Iztapalapa, CDMX, México; 4Departamento de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México, CDMX, México; 5Department of Psychology, University of Washington Guthrie Hall (GTH), Seattle, WA, USA; 6Departamento de Neuromorfología Funcional, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, CDMX, México; 7Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada; 8Department of Psychiatry, University of Toronto, Toronto, ON, Canada; 9Laboratorio de Psiquiatría Experimental, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, CDMX, MéxicoCorrespondence: Francisco Pellicer, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México Xochimilco 101, San Lorenzo Huipulco, Alcaldía Tlalpan, CDMX, 14370, México, Tel +52 55 41605063, Email pellicer@imp.edu.mxObjective: Pain constitutes an essential alarm for preserving the organism’s integrity. Damage to the nervous system produces a pathological condition known as neuropathic pain.Purpose: Blood oxygenation level-dependent (BOLD) and functional magnetic resonance imaging (fMRI) have been widely used to map neuroanatomy and the active regions of interest (ROI) of nociceptive processing. Our study explored the brain’s BOLD response in rats after thermal noxious stimulation, immediately after sciatic nerve damage and during 75 minutes after surgical lesion of the sciatic nerve.Methods: Nine male Wistar rats were tested; the experiments were performed on a 7-Tesla /21-cm Varian Agilent system. This approach allowed, for the first time, to measure in vivo the BOLD changes in brain regions involved with the pain process: cingulated (ACC), somatosensory (S1), and insular cortices (IC), as well as thalamus (Th) and ventral tegmental area (VTA) related with acute thermal pain and during the early stages of sciatic denervation that produce neuropathic pain.Results: During thermonociception scan, all subjects showed BOLD activation in the ROIs determined as ACC, S1, Th, IC and VTA. After denervation, these regions continued to show activation with a slow decrement in intensity for the duration of the experiment. The results suggest that these brain structures are overactive during the genesis of neuropathic pain.Conclusion: The study shows for the first time continuous activation of the pain matrix following an acute thermal nociceptive stimulus followed by neuropathic damage. These results have given insight into the early stages of the development of neuropathic pain in vivo.Keywords: fMRI, resting state, neuropathic pain, pain matrix, chronic pain, acute pain

The role of nitric oxide as a neurotransmitter in the olfactory and chemoreception systems of invertebrates has been well documented. This suggests an early and efficient sensory detection system that is evolutionarily preserved in various species, including vertebrates and invertebrates. Additionally, the presence of a nitric oxide neurotransmitter system has been reported in molluscs, particularly in octopus species. In this work, we present evidence for the existence of nitric oxide synthase in neurons and fibers, as well as its anatomical localization in various nuclei involved in chemosensory integration and the motor responses associated with these processes in Octopus maya., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Pain is a morbidity or comorbidity with a high incidence that significantly impacts the well-being of patients. In this study, we evaluated the effects of systemic administration of tramadol, a weak mu-opioid receptor (MOR) agonist, plus quinpirole (a D2-like receptor agonist). The study was performed in naïve rats and in rats with induced inflammatory and neuropathic pain. To measure the antinociceptive effect of the drugs, thermonociceptive and mechanonociceptive stimuli were applied and the emotional aspects of pain were evaluated using conditional place preference (CPP) experiments. Systemic quinpirole produced an antinociceptive effect only in naïve male rats. In naïve female animals, a small but significant pronociceptive effect was observed following quinpirole application. Tramadol plus quinpirole in male animals reversed allodynia and hyperalgesia induced by inflammatory and neuropathic insults, which were not alleviated by either drug alone. CPP experiments revealed that systemic quinpirole plus tramadol treatment was effective only in an inflammatory pain model. To evaluate whether tolerance to the antinociceptive effect was prevented by the combination of the drugs, a repeated administration five-day trial of tramadol plus quinpirole was evaluated under inflammatory pain conditions; quinpirole only slightly prevented the antinociceptive tolerance of MOR agonists. D2-like agonists are effective adjuvants for treating painful conditions in combination with a low dose of MOR agonists. Our results could lead to an investigation of whether these dopaminergic drugs in combination with opioids might reduce the MOR agonist dose while obtaining a higher analgesic effect with fewer side effects in humans., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The insular cortex (IC) is a brain region that both receives relevant sensory information and is responsible for emotional and cognitive processes, allowing the perception of sensory information. The IC has connections with multiple sites of the pain matrix, including cortico-cortical interactions with the anterior cingulate cortex (ACC) and top-down connections with sites of descending pain inhibition. We explored the changes in the extracellular release of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), after inflammation was induced by carrageenan injection. Additionally, we explored the role of 5HT receptors (the 5HT1A, 5HT2A, and 5HT3 receptors) in the IC after inflammatory insult. The results showed an increase in the extracellular levels of 5HT and 5-HIAA during the inflammatory process compared to physiological levels. Additionally, the 5HT1A receptor was overexpressed. Finally, the 5HT1A, 5HT2A, and 5HT3 receptor blockade in the IC had antinociceptive effects. Our results highlight the role of serotonergic neurotransmission in long-lasting inflammatory nociception within the IC.

Raphanus sativus L. cv. Sango, commonly known as red radish , is widely consumed around the world as a vegetable, but its benefit in pain relief is not sufficiently investigated. This study aimed to evaluate the antinociceptive effects of R. sativus and a possible mechanism of action. An aqueous extract of R. sativus sprouts (AERSS) was investigated by parenteral (10, 30, and 100 mg kg -1 , i.p.) and enteral (500 mg kg -1 , p.o.) administration in the neurogenic and inflammatory phases of the formalin test, where gastric damage was also evaluated as a possible adverse effect. Ketorolac (5 mg kg -1 , i.p.) was used as the reference drug. Endogenous opioid and 5-HT1A serotonin receptors, as well as the cAMP/NO-cGMP pathways, were explored in the study of a possible mechanism of action by using their corresponding antagonists: naloxone, 1 mg kg -1 , i.p., WAY100635, 1 mg kg -1 , i.p., and enzymatic activators or inhibitors, respectively. Sulforaphane (SFN), a known bioactive metabolite, was analyzed using electroencephalography (EEG) to evidence its central involvement. A significant and dose-dependent antinociceptive activity was observed with the AERSS resembling the antinociceptive effect of the reference drug, with an equivalent significant response with a dose of 500 mg kg -1 , p.o. without causing gastric damage. The participation of the endogenous opioid and 5-HT 1A serotonin receptors at central and peripheral levels was also observed, with a differential participation of cAMP/NO-cGMP. SFN as one metabolite produced significant changes in the EEG analysis, reinforcing its effects on the CNS. Our preclinical evidence supports the benefits of consuming Raphanus sativus cv. Sango sprouts for pain relief.

Natural products are recognized as potential analgesics since many of them are part of modern medicine to relieve pain without serious adverse effects. The aim of this study was to investigate the antinociceptive and anti-inflammatory activities of an aqueous extract of Brassica oleracea var. italica sprouts (AEBS) and one of its main reported bioactive metabolites sulforaphane (SFN). Antinociceptive activity of the AEBS (30, 100, and 300 mg/kg, i.p. or 1000 and 2000 mg/kg, p.o.) and SFN (0.1 mg/kg, i.p.) was evaluated in the plantar test in rats to reinforce its analgesic-like activity at central level using the reference drug tramadol (TR, 50 mg/kg, i.p.). The anti-inflammatory-like response was determined in the carrageenan-induced oedema at the same dosages for comparison with ketorolac (KET, 20 mg/kg, i.p.) or indomethacin (INDO, 20 mg/kg, p.o.). A histological analysis of the swollen paw was included to complement the anti-inflammatory response. Additionally, acute toxicity observed in clinical analgesics as the most common adverse effects, such as sedation and/or gastric damage, was also explored. As a result, central and peripheral action of the AEBS was confirmed using enteral and parenteral administration, in which significant reduction of the nociceptive and inflammatory responses resembled the effects of TR, KET, or INDO, respectively, involving the presence of SFN. No adverse or toxic effects were observed in the presence of the AEBS or SFN. In conclusion, this study supports that Brassica oleracea var. italica sprouts are a potential source of antinociceptive natural products such as SFN for therapy of pain alone and associated to an inflammation condition., (© 2023. The Author(s).)

Salvia amarissima Ortega is an endemic species of Mexico used in folk medicine to alleviate pain and as a nervous tranquilizer. The S. amarissima extract and one of its abundant metabolites, identified and isolated through chromatographic techniques, were investigated to obtain scientific evidence of its potential effects to relieve nociplastic pain such as fibromyalgia. Then, the extract and amarisolide A (3-300 mg/kg, i.p.) were pharmacologically evaluated in reserpine-induced fibromyalgia-type chronic pain and in depressive-like behavior (as a common comorbidity) by using the forced swimming test in rats. The 5-HT 1A serotonin receptor (selective antagonist WAY100635, 1 mg/kg, i.p.) was explored after the prediction of a chemical interaction using in silico analysis to look for a possible mechanism of action of amarisolide A. Both the extract and amarisolide A produced significant and dose-dependent antihyperalgesic and antiallodynic effects in rats, as well as significant antidepressive behavior without sedative effects when the antinociceptive dosages were used. The 5-HT 1A serotonin receptor participation was predicted by the in silico descriptors and was corroborated in the presence of WAY100635. In conclusion, S. amarissima possesses antihyperalgesic, antiallodynic, and anti-depressive activities, partially due to the presence of amarisolide A, which involves the 5-HT 1A serotonin receptor. This pharmacological evidence suggests that S. amarissima and amarisolide A are both potential alternatives to relieve pain-like fibromyalgia.

Rationale: Exposure of male rats to an inaccessible receptive female and copulation increases dopamine (DA) levels in the nucleus accumbens (NAcc). Males copulating to satiety become sexually inhibited and most of them do not display sexual activity when presented with a sexually receptive female 24 h later. This inhibitory state can be pharmacologically reversed. There are no studies exploring NAcc DA levels during this sexual inhibitory state., Objectives: To characterize changes in NAcc DA and its metabolites' levels during sexual satiety development, during the well-established sexual inhibitory state 24 h later, and during its pharmacological reversal., Methods: Changes in NAcc DA and its metabolites were measured in sexually experienced male rats, using in vivo microdialysis, during copulation to satiety, when presented to a new sexually receptive female 24 h later, and during the pharmacological reversal of the sexual inhibition by anandamide., Results: NAcc DA levels remained increased during copulation to satiety. DA basal levels were significantly reduced 24 h after copulation to satiety, as compared to the initial basal levels. Presenting a receptive female behind a barrier 24 h after satiety did not induce the typical NAcc DA elevation in the sexually satiated males but there was a decrease that persisted when they got access to the female, with which they did not copulate. Anandamide injection slightly increased NAcc DA levels coinciding with sexual satiety reversal., Conclusions: Reduced NAcc DA concentrations coincide with the inhibition of an instinctive, natural rewarding behavior suggesting that there might be a DA concentration threshold needed to be responsive to a rewarding stimulus., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fibromyalgia (FM) is a pain syndrome characterized by chronic widespread pain and CNS comorbidities. Tilia americana var. mexicana is a medicinal species used to treat anxiety, insomnia, and acute or chronic pain. However, its spectrum of analgesic efficacy for dysfunctional pain is unknown. To investigate a possible therapeutic alternative for FM-type pain, an aqueous Tilia extract (TE) and its flavonoid fraction (FF) containing rutin and isoquercitrin were evaluated alone and/or combined with clinical drugs (tramadol-TRA and pramipexol-PRA) using the reserpine-induced FM model in rats. Chromatographic analysis allowed the characterization of flavonoids, while a histological analysis confirmed their presence in the brain. TE (10-100 mg/kg, i.p.) and FF (10-300 mg/kg, i.p.) produced significant and dose-dependent antihyperalgesic and antiallodynic effects equivalent to TRA (3-10 mg/kg, i.p.) or PRA (0.01-1 mg/kg, s.c.). Nevertheless, the combination of FF + TRA or FF + PRA resulted in an antagonistic interaction by possible competitive action on the serotonin transporter or µ-opioid and D 2 receptors, respectively, according to the in silico analysis. Flavonoids were identified in cerebral regions because of their self-epifluorescence. In conclusion, Tilia possesses potential properties to relieve FM-type pain. However, the consumption of this plant or flavonoids such as quercetin derivatives in combination with analgesic drugs might reduce their individual benefits.